Diabetes is the fifth most common cause of death and was responsible for over 5% of worldwide deaths in 2000 (Roglic, G.: Unwin, N.; Bennett, P. H.; Mathers, C.; Tuomilehto, J.; Nag, S.; Connelly, V.; King, H; Diabetes Care 2005, 28, 2130-2135). Type II Diabetes is characterized by insulin resistance of the peripheral tissues, including the skeletal muscle, liver, and adipose. The resulting hyperglycemia is often accompanied by defective lipid metabolism that can lead to cardiovascular complications such as atherosclerosis and hypertension. Accordingly, it often leads to serious complications such as renal disease, blindness, heart disease and stroke, and the treatment of diabetes annually incurs nearly 100 billion dollars of medical costs in the United States alone (Saltiel, A. R.; Cell 2001, 104, 517-529).
The most broadly successful class of drugs used to treat type II diabetes is the thiazolidinediones (TZDs), some examples of which are pioglitazone and rosiglitazone (trade names Actos and Avandia, respectively). The antidiabetic activity of TZDs was first elucidated in the 1970s, where they were first identified as high affinity ligands for the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) (Colca, J. R.; Kletzien, R. F.; Expert Opin. Invest. Drugs 2006, 15, 205-210, Lehmann, J. M.; Moore, L. B.; Smitholiver, T. A.; Wilkison, W. O.; Willson, T. M.; Kliewer, S. A., J. Biol. Chem. 1995, 270, 12953-12956).
However, the link between TZDs, PPARγ, and antidiabetic benefits came into question and ultimately led to the identification of a previously unknown outer mitochondrial membrane protein that directly binds to TZDs (Colca, J. R.; Kletzien, R. F., Expert Opin. Invest.; Drugs 2006, 15, 205-210, Also known as CISD1 (CDGSH Iron Sulfur Domain 1), ZCD1, C10orf70, MGC14684, MDS029, Colca, J. R.; McDonald, W. G.; Waldon, D. J.; Leone J. W.; Lull, J. M.; Bannow, C. A.; Lund, E. T.; Mathews, W. R., Am. J. Physio.; Endocrinol. Metab. 2004, 286, E252-E260). The outer mitochondrial membrane protein was named mitoNEET based on its subcellular localization (mito) and the presence of the amino acid sequence Asn-Glu-Glu-Thr (NEET).
MitoNEET is an integral protein of the outer mitochondrial membrane (OMM), as shown by immuno-electron microscopy and fractionation of highly purified rat liver mitochondria. An amino terminal signal sequence within the first 32 residues, containing a predicted transmembrane domain, targets mitoNEET to the outer membrane. The orientation of mitoNEET towards the cytoplasm was established by proteolytic digestion of the protein on intact rat liver mitochondria.
Mitochondrial dysfunction has been further associated with insulin resistance and the development of type II diabetes (Stark, R. & Roden, M. (2007) Eur. Clin. Invest. 37, 236-248). Some studies indicate that disease pathogenesis involves diminished mitochondrial oxidative capacity in insulin sensitive tissues, and agents, such as TZDs, are known to enhance oxidative capacity and normalize lipid metabolism (Bandyopadhyay, G K, Yu, J G, Ofrecio, J, & Olefsky, J M (2006) Diabetes 55, 2277-2285; Bogacka, I, Xie, H, Bray, G A, & Smith, S R (2005) Diabetes 54, 1392-1399). Moreover, deficiency of mitoNEET in mice results in a compromise in the respiratory capacity of heart mitochondria (Wiley, S E, Murphy, A N, Ross, S A, van der Geer, P, & Dixon, J E (2007) PNAS 104, 5318-5323). Accordingly, mitoNEET is a candidate target for drugs to treat several disorders including type II diabetes.